Osteoarthritis (OA) is the most common form of arthritis and remains one of the few chronic diseases of aging for which there is little if any effective treatment and few preventive strategies. Symptomatic knee osteoarthritis affects 12% of elders and despite medical advances, remains, for many affected, a major source of pain and function limitation. The MOST study is the first large scale observational study to focus on persons with or at high risk of knee osteoarthritis. The central goal of MOST is to identify modifiable risk factors. To accomplish this, we recruited and have followed 3026 persons who either had knee osteoarthritis at baseline or were at high risk of developing disease because they had one or more disease risk factors. We are proposing a renewal of MOST. In continuing to follow this unique cohort, we will address a series of new questions representing three investigative themes: mechanical risk factors, causes of knee symptoms and long term disease trajectory. The focus on risk factors which affect knees on the basis of loading reflects the view of MOST investigators that OA is a mechanically driven disease. Mechanical risk factors are likely to be both strongly associated with disease risk and modifiable. Pain is the cardinal symptom of OA and the main cause of its clinical and public health impact. An investigation of pain sensitivity seeks to better understand the neurological mechanisms that sustain or magnify OA symptoms. Another symptom associated with knee OA is knee buckling, whose frequency and impact has only recently been described and whose association with falls and fractures in older adults is unknown. Lastly, we will take advantage of two grant cycles of comprehensive information on functional loss and repeated MRI's to address the long term trajectory of this chronic disease. In this renewal of the MOST study we will re-examine a group of persons who already have disease or are at high risk of getting it, to evaluate the risk factors for disease. Those factors that prove to be related to disease development or progression could then be targeted for risk factor modification offering unique opportunities for disease prevention. Risk factors to be studied include many which are practical to modify, including strength, ways of walking, and balance. Also, MOST will provide the best understanding yet of the relation between changes in knee structures and their effects on pain and function, providing structural targets for treatment. [unreadable] [unreadable] [unreadable]